Inhibitors of IMPDH enzyme

ABSTRACT

The present invention relates to a novel class of compounds which are IMPDH inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting IMPDH enzyme activity and consequently, may be advantageously used as therapeutic agents for IMPDH mediated processes. This invention also relates to methods for inhibiting the activity of IMPDH using the compounds of this invention and related compounds.

RELATED U.S. APPLICATION DATA

[0001] This application is a divisional of application Ser. No.09/556,253, filed Apr. 24, 2000, which is a divisional of applicationSer. No. 08/832,165, filed Apr. 2, 1997 (now U.S. Pat. No. 6,054,472),which is a Continuation-in-Part of application Ser. No. 08/801,780,filed Feb. 14, 1997 (now U.S. Pat. No. 6,344,465), which is aContinuation-in-Part of application Ser. No. 08/636,361, filed Apr. 23,1996 (now U.S. Pat. No. 5,807,876).

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to a novel class of compounds whichinhibit IMPDH. This invention also relates to pharmaceuticalcompositions comprising these compounds. The compounds andpharmaceutical compositions of this invention are particularly wellsuited for inhibiting IMPDH enzyme activity and consequently, may beadvantageously used as therapeutic agents for IMPDH mediated processes.This invention also relates to methods for inhibiting the activity ofIMPDH using the compounds of this invention and related compounds.

BACKGROUND OF THE INVENTION

[0003] The synthesis of nucleotides in organisms is required for thecells in those organisms to divide and replicate. Nucleotide synthesisin mammals may be achieved through one of two pathways: the de novosynthesis pathway or the salvage pathway. Different cell types use thesepathways to a different extent.

[0004] Inosine-5′-monophosphate dehydrogenase (IMPDH; EC 1.1.1.205) isan enzyme involved in the de novo synthesis of guanosine nucleotides.IMPDH catalyzes the NAD-dependent oxidation of inosine-5′-monophosphate(IMP) to xanthosine-′5-monophosphate (XMP) [Jackson R. C. et. al.,Nature, 256, pp. 331-333, (1975)].

[0005] IMPDH is ubiquitous in eukaryotes, bacteria and protozoa [Y.Natsumeda & S. F. Carr, Ann. N.Y. Acad., 696, pp. 88-93 (1993)]. Theprokaryotic forms share 30-40% sequence identity with the human enzyme.Regardless of species, the enzyme follows an ordered Bi-Bi reactionsequence of substrate and cofactor binding and product release. First,IMP binds to IMPDH. This is followed by the binding of the cofactor NAD.The reduced cofactor, NADH, is then released from the product, followedby the product, XMP [S. F. Carr et al., J. Biol. Chem., 268, pp.27286-90 (1993); E. W. Holmes et al., Biochim. Biophys. Acta, 364, pp.209-217 (1974)]. This mechanism differs from that of most other knownNAD-dependent dehydrogenases, which have either a random order ofsubstrate addition or require NAD to bind before the substrate.

[0006] Two isoforms of human IMPDH, designated type I and type II, havebeen identified and sequenced [F. R. Collart and E. Huberman, J. Biol.Chem., 263, pp. 15769-15772, (1988); Y. Natsumeda et. al., J. Biol.Chem., 265, pp. 5292-5295,(1990)]. Each is 514 amino acids, and theyshare 84% sequence identity. Both IMPDH type I and type II form activetetramers in solution, with subunit molecular weights of 56 kDa [Y.Yamada et. al., Biochemistry, 27, pp. 2737-2745 (1988)].

[0007] The de novo synthesis of guanosine nucleotides, and thus theactivity of IMPDH, is particularly important in B and T-lymphocytes.These cells depend on the de novo, rather than salvage pathway togenerate sufficient levels of nucleotides necessary to initiate aproliferative response to mitogen or antigen [A. C. Allison et. al.,Lancet II, 1179,(1975) and A. C. Allison et. al., Ciba Found. Symp., 48,207,(1977)]. Thus, IMPDH is an attractive target for selectivelyinhibiting the immune system without also inhibiting the proliferationof other cells.

[0008] Immunosuppression has been achieved by inhibiting a variety ofenzymes including for example, the phosphatase calcineurin (inhibited bycyclosporin and FK-506); dihydroorotate dehydrogenase, an enzymeinvolved in the biosynthesis of pyrimidines (inhibited by leflunomideand brequinar); the kinase FRAP (inhibited by rapamycin); and the heatshock protein hsp70 (inhibited by deoxyspergualin). [See B. D. Kahan,Immunological Reviews, 136, pp. 29-49 (1993); R. E. Morris, The Journalof Heart and Lung Transplantation, 12(6), pp. S275-S286 (1993)].

[0009] Inhibitors of IMPDH are also known. U.S. Pat. No. 5,380,879 and5,444,072 and PCT publications WO 94/01105 and WO 94/12184 describemycophenolic acid (MPA) and some of its derivatives as potent,uncompetitive, reversible inhibitors of human IMPDH type I (K_(i)=33 nM)and type II (K_(i)=9nM). MPA has been demonstrated to block the responseof B and T-cells to mitogen or antigen [A. C. Allison et. al., Ann. N.Y. Acad. Sci., 696, 63,(1993).

[0010] Immunosuppressants, such as MPA, are useful drugs in thetreatment of transplant rejection and autoimmune diseases. [R. E.Morris, Kidney Intl., 49, Suppl. 53,S-26,(1996)]. However, MPA ischaracterized by undesirable pharmacological properties, such asgastrointestinal toxicity and poor bioavailability. [L. M. Shaw, et.al., Therapeutic Drug Monitoring, 17, pp. 690-699,(1995)].

[0011] Nucleoside analogs such as tiazofurin, ribavirin and mizoribinealso inhibit IMPDH [L. Hedstrom, et. al. Biochemistry, 29, pp. 849-854(1990)]. These compounds, which are competitive inhibitors of IMPDH,suffer from lack of specificity to this enzyme.

[0012] Mycophenolate mofetil, a prodrug which quickly liberates free MPAin vivo, was recently approved to prevent acute renal allograftrejection following kidney transplantation. [L. M. Shaw, et. al.,Therapeutic Drug Monitoring, 17, pp. 690-699, (1995); H. W. Sollinger,Transplantation, 60, pp. 225-232 (1995)]. Several clinical observations,however, limit the therapeutic potential of this drug. [L. M. Shaw, et.al., Therapeutic Drug Monitoring, 17, pp. 690-699,(1995)]. MPA israpidly metabolized to the inactive glucuronide in vivo. [A. C., Allisonand E. M. Eugui, Immunological Reviews, 136, pp. 5-28 (1993)]. Theglucuronide then undergoes enterohepatic recycling causing accumulationof MPA in the gastrointestinal tract where it cannot exert its IMPDHinhibitory activity on the immune system. This effectively lowers thedrug's in vivo potency, while increasing its undesirablegastrointestinal side effects.

[0013] It is also known that IMPDH plays a role in other metabolicevents. Increased IMPDH activity has been observed in rapidlyproliferating human leukemic cell lines and other tumor cell lines,indicating IMPDH as a target for anti-cancer as well asimmunosuppressive chemotherapy [M. Nagai et. al., Cancer Res., 51, pp.3886-3890, (1991)]. IMPDH has also been shown to play a role in theproliferation of smooth muscle cells, indicating that inhibitors ofIMPDH, such as MPA or rapamycin, may be useful in preventing restenosisor other hyperproliferative vascular diseases [C. R. Gregory et al.,Transplantation, 59, pp. 655-61 (1995); PCT publication WO 94/12184; andPCT publication WO 94/01105].

[0014] Additionally, IMPDH has been shown to play a role in viralreplication in some viral cell lines. [S. F. Carr, J. Biol. Chem., 268,pp. 27286-27290 (1993)]. Analogous to lymphocyte and tumor cell lines,the implication is that the de novo, rather than the salvage, pathway iscritical in the process of viral replication.

[0015] The IMPDH inhibitor ribavirin is currently being evaluated forthe treatment of hepatitis C virus (HCV) and hepatitis B virus (HBV)infection and disease. Ribavirin enhances the sustained efficacy ofinterferon in HBV and HCV treatment. However, the therapeutic potentialof ribavirin is limited by its lack of a sustained response inmonotherapy and broad cellular toxicity.

[0016] Thus, there remains a need for potent IMPDH inhibitors withimproved pharmacological properties. Such inhibitors would havetherapeutic potential as immunosuppressants, anti-cancer agents,anti-vascular hyperproliferative agents, antiinflammatory agents,antifungal agents, antipsoriatic and anti-viral agents.

SUMMARY OF THE INVENTION

[0017] The present invention provides compounds, and pharmaceuticallyacceptable derivatives thereof, that are useful as inhibitors of IMPDH.These compounds can be used alone or in combination with othertherapeutic or prophylactic agents, such as anti-virals,antiinflammatory agents, antibiotics, and immunosuppressants for thetreatment or prophylaxis of transplant rejection and autoimmune disease.Additionally, these compounds are useful, alone or in combination withother agents, as therapeutic and prophylactic agents for antiviral,anti-tumor, anti-cancer, antiinflammatory agents, antifungal agents,antipsoriatic immunosuppressive chemotherapy and restenosis therapyregimens.

[0018] The invention also provides pharmaceutical compositionscomprising the compounds of this invention, as well as multi-componentcompositions comprising additional IMPDH compounds together with animmunosuppressant. The invention also provides methods of using thecompounds of this invention, as well as other related compounds, for theinhibition of IMPDH.

[0019] The compounds of this invention, as well as those used in themethods of this invention demonstrate a different metabolic profile thanMPA and its derivatives. Because of this difference, methods of thisinvention and the compounds used therein may offer advantages astherapeutics for IMPDH mediated disease. These advantages includeincreased overall therapeutic benefit and reduction in deleterious sideeffects.

DETAILED DESCRIPTION OF THE INVENTION

[0020] In order that the invention herein described may be more fullyunderstood, the following detailed description is set forth. In thedescription, the following abbreviations are used: Designation Reagentor Fragment Ac acetyl Me methyl Et ethyl Bn benzyl CDIcarbonyldiimidazole DIEA diisopropylethylamine DMAPdimethylaminopyridine DMF dimethylformamide DMSO dimethylsulfoxide EDC1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride EtOAc ethylacetate THF tetrahydrofuran

[0021] The following terms are employed herein:

[0022] Unless expressly stated to the contrary, the terms “—SO₂—” and“—S(O)₂—” as used herein refer to a sulfone or sulfone derivative (i.e.,both appended groups linked to the S), and not a sulfinate ester.

[0023] The terms “halo” or “halogen” refer to a radical of fluorine,chlorine, bromine or iodine.

[0024] The term “immunosuppressant” refers to a compound or drug whichpossesses immune response inhibitory activity. Examples of such agentsinclude cyclosporin A, FK506,rapamycin, leflunomide, deoxyspergualin,prednisone, azathioprine, mycophenolate mofetil, OKT3,ATAG, interferonand mizoribine.

[0025] The term “interferon” refers to all forms of interferons,including but not limited to alpha, beta and gamma forms.

[0026] IMPDH-mediated disease refers to any disease state in which theIMPDH enzyme plays a regulatory role in the metabolic pathway of thatdisease. Examples of IMPDH-mediated disease include transplant rejectionand autoimmune diseases, such as rheumatoid arthritis, multiplesclerosis, juvenile diabetes, asthma, and inflammatory bowel disease, aswell as inflammatory diseases, cancer, viral replication diseases andvascular diseases.

[0027] For example, the compounds, compositions and methods of usingthem of this invention may be used in the treatment of transplantrejection (e.g., kidney, liver, heart, lung, pancreas (islet cells),bone marrow, cornea, small bowel and skin allografts and heart valvexenografts) and autoimmune diseases, such as rheumatoid arthritis,multiple sclerosis, juvenile diabetes, asthma, inflammatory boweldisease (Crohn's disease, ulcerative colitus), lupus, diabetes, mellitusmyasthenia gravis, psoriasis, dermatitis, eczema, seborrhoea, pulmonaryinflammation, eye uveitis, hepatitis, Grave's disease, Hashimoto'sthyroiditis, Behcet's or Sjorgen's syndrome (dry eyes/mouth), perniciousor immunohaemolytic anaemia, idiopathic adrenal insufficiency,polyglandular autoimmune syndrome, and glomerulonephritis, scleroderma,lichen planus, viteligo (depigmentation of the skin), autoimmunethyroiditis, and alveolitis, inflammatory diseases such asosteoarthritis, acute pancreatitis, chronic pancreatitis, asthma andadult respiratory distress syndrome, as well as in the treatment ofcancer and tumors, such as solid tumors, lymphomas and leukemia,vascular diseases, such as restenosis, stenosis and artherosclerosis,and DNA and RNA viral replication diseases, such as retroviral diseases,and herpes.

[0028] Additionally, IMPDH enzymes are also known to be present inbacteria and thus may regulate bacterial growth. As such, theIMPDH-inhibitor compounds, compositions and methods described herein maybe useful in treatment or prevention of bacterial infection, alone or incombination with other antibiotic agents.

[0029] The term “treating” as used herein refers to the alleviation ofsymptoms of a particular disorder in a patient or the improvement of anascertainable measurement associated with a particular disorder. As usedherein, the term “patient” refers to a mammal, including a human.

[0030] The term “thiocarbamates” refers to compounds containing thefunctional group N—SO₂—O.

[0031] The terms “HBV”, “HCV” and “HGV” refer to hepatitis-B virus,hepatitis-C virus and hepatitis-G virus, respectively.

[0032] According to one embodiment, the invention provides methods ofinhibiting IMPDH activity in a mammal comprising the step ofadministering to said mammal, a compound of formula I:

[0033] wherein:

[0034] A is selected from:

[0035] (C₁-C₆)-straight or branched alkyl, or (C₂-C₆)-straight orbranched alkenyl or alkynyl; and A optionally comprises up to 2substituents, wherein:

[0036] the first of said substituents, if present, is selected from R¹or R³, and

[0037] the second of said substituents, if present, is R¹;

[0038] B is a saturated, unsaturated or partially saturated monocyclicor bicyclic ring system optionally comprising up to 4 heteroatomsselected from N, O, or S and selected from the formulae:

[0039] wherein each X is the number of hydrogen atoms necessary tocomplete proper valence; and B optionally comprises up to 3substituents,

[0040] wherein:

[0041] the first of said substituents, if present, is selected from R¹,R², R⁴ or R⁵,

[0042] the second of said substituents, if present, is selected from R¹or R⁴, and

[0043] the third of said substituents, if present, is R¹; and

[0044] D is selected from C(O), C(S), or S(O)₂;

[0045] wherein:

[0046] each R¹ is independently selected from 1,2-methylenedioxy,1,2-ethylenedioxy, R⁶ or (CH₂)_(n)—Y;

[0047] wherein n is 0, 1 or 2; and

[0048] Y is selected from halogen, CN, NO₂,CF₃, OCF₃, OH, SR⁶,S(O)R⁶,SO₂R⁶, NH₂, NHR⁶, N(R⁶)₂, NR⁶R⁸, COOH, COOR⁶ or OR⁶;

[0049] each R² is independently selected from (C₁-C₄)-straight orbranched alkyl, or (C₂-C₄)-straight or branched alkenyl or alkynyl; andeach R² optionally comprises up to 2 substituents, wherein:

[0050] the first of said substituents, if present, is selected from R¹,R⁴ and R⁵, and

[0051] the second of said substituents, if present, is R¹;

[0052] R³ is selected from a monocyclic or a bicyclic ring systemconsisting of 5 to 6 members per ring,

[0053] wherein said ring system optionally comprises up to 4 heteroatomsselected from N, O, or S, and wherein a CH₂ adjacent to any of said N,O, or S heteroatoms is optionally substituted with C(O); and each R³optionally comprises up to 3 substituents, wherein:

[0054] the first of said substituents, if present, is selected from R¹,R², R⁴ or R⁵,

[0055] the second of said substituents, if present, is selected from R¹or R⁴, and

[0056] the third of said substituents, if present, is R¹;

[0057] each R⁴ is independently selected from OR⁵, OC(O)R⁶, OC(O)R⁵,OC(O)OR⁶, OC(O)OR⁵, OC(O)N(R⁶)₂, OP(O)(OR⁶)₂, SR⁶, SR⁵, S(O)R⁶, S(O)R⁵,SO₂R⁶, SO₂R⁵, SO₂N(R⁶)₂, SO₂NR⁵R⁶, SO₃R6,C(O)R⁵, C(O)OR⁵, C(O)R⁶,C(O)OR⁶, NC(O)C(O)R⁶, NC(O)C(O)R⁵, NC(O)C(O)OR⁶, NC(O)C(O)N(R⁶)₂,C(O)N(R⁶)₂, C(O)N(OR⁶)R⁶, C(O)N(OR⁶)R⁵, C(NOR⁶)R⁶, C(NOR⁶)R⁵, N(R⁶)₂,NR⁶C(O)R¹, NR⁶C(O)R⁶, NR⁶C(O)R⁵, NR⁶C(O)OR⁶, NR⁶C(O)OR⁵, NR⁶C(O)N(R⁶)₂,NR⁶C(O)NR⁵R⁶, NR⁶SO₂R⁶, NR⁶SO₂R⁵, NR⁶SO₂N(R⁶)₂, NR6S0₂NR5R6,N(OR⁶)R⁶,N(OR⁶)R⁵, P(O) (OR⁶)N(R⁶)₂,and P(O) (OR⁶)₂;

[0058] each R⁵ is a monocyclic or a bicyclic ring system consisting of 5to 6 members per ring, wherein said ring system optionally comprises upto 4 heteroatoms selected from N, O, or S, and wherein a CH₂ adjacent tosaid N, O, or S maybe substituted with C(O); and each R⁵ optionallycomprises up to 3 substituents, each of which, if present, is R¹;

[0059] each R⁶ is independently selected from H, (C₁-C₄)-straight orbranched alkyl, or (C₂-C₄) straight or branched alkenyl; and each R⁶optionally comprises a substituent that is R⁷;

[0060] R⁷ is a monocyclic or a bicyclic ring system consisting of 5 to 6members per ring, wherein said ring system optionally comprises up to 4heteroatoms selected from N, O, or S, and wherein a CH₂ adjacent to saidN, O, or S maybe substituted with C(O); and each R⁷ optionally comprisesup to 2 substituents independently chosen from H, (C₁-C₄)-straight orbranched alkyl, (C₂-C₄) straight or branched alkenyl,1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH₂)_(n)-Z;

[0061] wherein n is 0, 1 or 2; and

[0062] Z is selected from halogen, CN, NO₂, CF₃, OCF₃, OH,S(C₁-C₄)-alkyl, SO(C₁-C₄)-alkyl, SO₂(C₁-C₄)-alkyl, NH₂,NH(C₁-C₄)-alkyl,N((C₁-C₄)-alkyl)₂, N((C₁-C₄)-alkyl)R⁸, COOH, C(O)O(C₁-C₄)-alkyl orO(C₁-C₄)-alkyl; and

[0063] R⁸ is an amino protecting group; and

[0064] wherein any carbon atom in any A, R² or R⁶ is optionally replacedby O, S, SO, SO₂,NH, or N(C₁-C₄)-alkyl.

[0065] The term “substituted” refers to the replacement of one or morehydrogen radicals in a given structure with a radical selected from aspecified group. When more than one hydrogen radical may be replacedwith a substituent selected from the same specified group, thesubstituents may be either the same or different at every position.

[0066] The term “monocyclic or bicyclic ring system consisting of 5 to 6members per ring” refers to 5 or 6 member monocyclic rings and 8, 9 and10 membered bicyclic ring structures, wherein each bond in each ring maybe possess any degree of saturation that is chemically feasible. Whensuch structures contain substituents, those substituents may be at anyposition of the ring system, unless otherwise specified.

[0067] As specified, such ring systems may optionally comprise up to 4heteroatoms selected from N, O, or S. Those heteroatoms may replace anycarbon atoms in these ring systems as long as the resulting compound ischemically stable.

[0068] The term “wherein each X is the number of hydrogen atomsnecessary to complete proper valence” means that X is 0, 1 or 2 hydrogenatoms, depending upon the identity of the ring atom to which X is bound(C, N, O, or S), the identity of the two adjacent ring atoms, and thenature of the bonds between the ring atom to which X is bound and thetwo adjacent ring atoms (single, double or triple bond). In essence,this definition is meant to exclude from X any substituents other thanhydrogen.

[0069] The term “amino protecting group” refers to a suitable chemicalgroup which may be attached to a nitrogen atom. The term “protected”refers to when the designated functional group is attached to a suitablechemical group (protecting group). Examples of suitable amino protectinggroups and protecting groups are described in T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley andSons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); L. Paquette, ed.Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995) and are exemplified in certain of the specific compounds used inthis invention.

[0070] According to another embodiment, the invention provides methodsof inhibiting IMPDH in mammals by administering a compound of theformula (II):

[0071] wherein B and D are as defined above.

[0072] More preferably, in methods employing the compounds of formulae(I) or (II), component B comprises from 0 to 2 substituents. Accordingto an alternate embodiment, the invention provides methods forinhibiting IMPDH in a mammal employing compounds (I) or (II), wherein Bcomprises at least a single substituent selected from the group definedby R⁵. Preferably, in this embodiment, B is a monocyclic aromatic ringcontaining at least one substituent which is also a monocyclic aromaticring.

[0073] The present invention also provides compounds which are useful ininhibiting IMPDH. According to one embodiment, the IMPDH inhibitorycompound has the formula (III):

[0074] wherein A, B and D are as defined above;

[0075] E is oxygen or sulfur; and

[0076] G and G′ are independently selected from R¹ or hydrogen.

[0077] According to an alternate embodiment, the invention provides acompound of the formula (IV):

[0078] wherein B, D, E, G and G′ are defined as above and B′ is asaturated, unsaturated or partially saturated monocyclic or bicyclicring system optionally comprising up to 4 heteroatoms selected from N,O, or S and selected from the formulae:

[0079] wherein each X is the number of hydrogen atoms necessary tocomplete proper valence; and B′ optionally comprises up to 3substituents, wherein:

[0080] the first of said substituents, if present, is selected from R¹,R², R⁴ or R⁵,

[0081] the second of said substituents, if present, is selected from R¹or R⁴, and

[0082] the third of said substituents, if present, is R¹; wherein X, R¹,R², R⁴ and R⁵ are defined as above.

[0083] Excluded from this invention are compounds of formula (IV)wherein B and B′ are simultaneously unsubstituted phenyl and compoundswherein B is unsubstituted phenyl and B′ is tri-chloro-, tri-bromo ortri-iodo phenyl.

[0084] Preferably, in compounds of formula (IV), B and B′ are phenylgroups comprising at least one substituent each. These compounds arerepresented by formula (V):

[0085] wherein K is selected from R¹ or R⁴; and J is selected from R¹,R² or R⁴.

[0086] Preferred compounds of formula (V) are those wherein D is —C(O)—,those wherein E is oxygen; those wherein J is NR⁶C(O)R⁵ or NR⁶C(O)R⁶,preferably NR⁶C(O)R⁶, more preferably N(CH₃)C(O)R⁶, and more preferablyN(CH₃)C(O)CH₃; those wherein K is (CH₂)_(n)—Y, preferably OCH₃ (i.e., nis 0, Y is OR⁶, and R⁶ is CH₃); and those wherein G is hydrogen. Morepreferred compounds of formula (V) are those wherein:

[0087] E is oxygen

[0088] J is NR⁶C(O)R⁵ or NR⁶C(O)R⁶;

[0089] K is (CH₂)_(n)—Y; and

[0090] G is hydrogen.

[0091] Even more preferred compounds of formula (V) are those wherein:

[0092] D is —C(O)—;

[0093] E is oxygen;

[0094] J is NR⁶C(O)R⁶;

[0095] K is OCH₃; and

[0096] G is hydrogen.

[0097] Most preferably in such compounds, J is N(CH₃)C(O)R⁶.

[0098] Alternate preferred compounds are those of formula V: wherein Jis R², those wherein D is —C(O)—, those-wherein E is oxygen, thosewherein J is R² substituted with R⁴′ preferably wherein R⁴ is NR⁶C(O)OR⁵or NR⁶C(O)OR⁶, more preferably wherein R⁴ is NR⁶C(O)OR⁵, more preferablywherein R is NHC(O)OR⁵, and more preferably wherein R is NHC(O)O—3-tetrahydrofuranyl, those wherein K is (CH₂)_(n)—Y, preferablywherein K is OCH₃, those wherein G is hydrogen, and those wherein:

[0099] D is —C(O)—;

[0100] E is oxygen;

[0101] K is OCH₃; and

[0102] G is hydrogen.

[0103] Alternatively, other preferred compounds include those of formulaVI:

[0104] those compounds of formula VI wherein K is OCH₃, and thosecompounds of formula VI wherein G is hydrogen.

[0105] An alternate embodiment of this invention is compounds of formulaV wherein K is selected from R¹ or R⁴; and J is selected from R¹, R²,R⁴, and R⁹ wherein, R¹, R², and R⁴, are as defined above and R⁹ isindependently selected from (C₁-C₄)-straight or branched alkyl, or(C₂-C₄)-straight or branched alkenyl or alkynyl; and each R⁹ optionallycomprises up to 2 substituents selected from NR⁶C(O)OR¹⁰, wherein R6 isas defined above and R¹⁰ is selected from (C₁-C₅)-straight or branchedalkyl optionally comprising up to two substituents selected from NR⁶R⁸,SR⁶, SO₂R⁶, —(CH₂)_(n)—SR⁶, —(CH₂)_(n)—OR⁶, and OR⁶, wherein n, R⁶ andR⁸, are as defined above.

[0106] In another embodiment, preferred compounds are those of formulaVII:

[0107] wherein K is selected from R¹ and R⁴; and A, D, R¹ and R⁴ areeach independently as defined in claim 1.

[0108] More preferred compounds of formula VII are those wherein D is—C(O)—, those wherein A is a monocyclic aromatic ring substituted with1-2 substituents selected from the group consisting of NR⁶C(O)R⁶,NR⁶C(O)R⁵, CH₂NR⁶C(O)OR⁶, and CH₂NR⁶C(O)OR⁵, those wherein A is amonocyclic aromatic ring substituted with 1-2 substituents selected fromthe group consisting of CH₂NR⁶C(O)OR⁶ and CH₂NR⁶C(O)OR⁵, those A is amonocyclic aromatic ring substituted with CH₂NR⁶C(O)OR⁵′ those wherein Ais a monocyclic aromatic ring substituted with CH₂NHC(O)OR⁵, thosewherein A is a monocyclic aromatic ring substituted withCH₂NHC(O)O-3-tetrahydrofuryl, those wherein K is (CH₂)_(n)—Y, thosewherein Kis OCH ₃, and those wherein:

[0109] A is a monocyclic aromatic ring substituted withCH₂NHC(O)O-3-tetrahydrofuryl; and

[0110] K is OCH₃.

[0111] Alternatively, other preferred compounds of this inventioninclude those compounds of formula VIII:

[0112] wherein D and K are as defined in claim 1.

[0113] Another embodiment is those compounds of formula IX:

[0114] wherein:

[0115] D is selected from C(O), C(S) and S(O)₂;

[0116] K is selected from R¹ and R⁴; and

[0117] J is selected from R¹, R², and R⁴.

[0118] More preferred compounds of formula IX include those wherein D is—C(O)—, those wherein J is NR⁶C(O)R⁵ or NR⁶C(O)R⁶, those wherein J isNR⁶C(O)R⁶, those wherein J is N(CH₃)C(O)R⁶, those wherein J isN(CH₃)C(O)CH₃, those wherein K is (CH₂)_(n)—Y, those wherein K is OCH₃,and those wherein:

[0119] K is OCH₃; and

[0120] J is N(CH₃)C(O)CH₃.

[0121] Tables IA, IB and IIB list preferred individual compounds of theinvention and preferred compounds employed in the compositions andmethods of this invention. Table IIA lists preferred compounds employedin the methods of this invention. TABLE IA

# G K A 1 H H benzyl

[0122] TABLE IB

# G K B′ 2 H H 3-methoxyphenyl 3 H H 3-thienyl 4 H H 3,4-difluorophenyl5 H H 2,5-dimethoxyphenyl 6 H H 3-methylthiophenyl 7 H H 3-bromophenyl 8H H 3-cyanophenyl 9 H H 3-trifluoromethyl-4- chlorophenyl 10 H H2-methyl-3-chlorophenyl 11 H H 2-methoxy-5-methylphenyl 12 H H2-methoxyphenyl 13 H H 3-methoxyphenyl 14 H H 2,5-dimethoxyphenyl 15 H H3-nitrophenyl 16 H H 4-nitrophenyl 17 H H 3-methylphenyl 18 H H3-trifluoromethylphenyl 19 H H 2-trifluoromethylphenyl 20 H H3-fluorophenyl 21 H H 4-phenoxyphenyl 22 H H 3-chlorophenyl 23 H H3-chloro-4-fluorophenyl 24 H H 3-aminophenyl 25 H H3-(hydroxymethyl)phenyl 26 H H 3-acetylenylphenyl 27 H H 3-hydroxyphenyl29 H H 3-pyridinyl 30 H H 4-pyridinyl 31 H H 2-(5-methyl)thiazolyl 39 HH 3,4-ethylenedioxyphenyl 40 H H 3-methyl-4-nitrophenyl 41 H H3-trifluoromethyl-4- nitrophenyl 42 H 3-chloro phenyl 43 H 3-chloro3-methylphenyl 44 — — — 45 H 3-fluoro phenyl 46 H 3-fluoro3-methylphenyl 47 H H 3-carbomethoxymethylphenyl 48 H H3-carboxyethylphenyl 49 H H 3-dimethylaminophenyl 50 H H 3-[2-(2-methyl)dioxolanyl]phenyl 51 H H 3-aminocarbonylphenyl 53 H H3-(3-furanyl)-phenyl 54 H H 3-carboxymethylphenyl 55 H 3-methoxy3-methylphenyl 56 H 3-methoxy 3-nitrophenyl 57 H 3-chloro3-carbomethoxymethylphenyl 58 H H 3-amino-5-methylphenyl 59 H 3-methoxy3-aminophenyl 60 H 3-bromo 3-methylphenyl 61 H 3-chloro 3-chloro-4-(5-oxazolyl)phenyl 62 H 3-chloro 4-(2-methylpyridyl) 63 H 3-chloro3-carboxymethylphenyl 64 H 3-bromo 3-nitrophenyl 65 H 3-bromo3-aminophenyl 66 H H 3-[5-(2- methylpyrimidinyl)]phenyl 67 H H3-(5-oxazolyl)phenyl 68 H 3-chloro 2-thienyl 69 H 3-chloro 3-thienyl 71H 3-chloro 3-methoxycarbamoyl-phenyl 72 H 3-chloro 3-acetamidophenyl 73H 3-chloro 3-iodophenyl 74 H 3-methyl phenyl 75 H 3-methyl3-methylphenyl 76 methyl 3-chloro 3-methylphenyl 77 methyl H3-methylphenyl 78 H 3-chloro 3-nitrophenyl 79 H 3-chloro 3-aminophenyl80 H H 3- (cyclohexylsulfamoyl)phenyl 81 H H 3-(methylsufamoyl)phenyl 82H H 3-(phenylsufamoyl)phenyl 83 H 3-methoxy 3-benzyloxycarbamoyl-phenyl84 H 3-methoxy 3-acetamidophenyl 85 H 3-chloro 4-(2-methyl)furanyl 86 H3-chloro 5-(2-methyl)thienyl 88 H 3-carbomethoxy 3-methylphenyl 89 H3-carbomethoxy 3-nitrophenyl 91 H 3-chloro 4-(2-nitro)thienyl 92 H3-chloro 4-(2-hydroxyamino)thienyl 93 H 3-chloro 3-(N-methyl)trifluoroacetamido- phenyl 94 H 3-chloro 3-(methylamino)phenyl 95H 3-chloro 4-(2-amino)thienyl 96 H 3-methoxy 3-trifluoroacetamidophenyl97 H 3-methoxy 3-(N- methyl)trifluoroacetamido- phenyl 98 H 3-methoxy3-(3′- picolyloxycarbamoyl)phenyl 99 H 3-methoxy3-(phenoxycarbamoyl)phenyl 100 H 3-methoxy 3-difluoroacetamidophenyl 101H 3- 3-methylphenyl acetoxymethyl 102 H 3- 3-methylphenyl hydroxymethyl104 H H 3-nitro-4-fluorophenyl 105 H 3-methoxy 3-(aminomethyl)phenyl[·TFA] 106 H 3-methoxy 5-(N-acetoxy)indolinyl 107 H 3-methoxy3-(N-methyl)acetamidophenyl 108 H 3-methoxy 3-[(2-oxo-2-(3,4,5-tri-methoxyphenyl)acetyl) amino]phenyl 109 H 3-amino 3-methylphenyl 110 H3-methoxy 3-benzamidophenyl 111 H 3-methoxy 3-phenylacetamidophenyl 112H 3-methoxy 3-phenylureidophenyl 113 H 3-methoxy 3-(t-butoxycarbamoylmethyl)phenyl 114 H 3-methoxy 3-(cyclopentylacetamido) phenyl 115 H3-methoxy 3-methylphenyl

[0123] TABLE IC

Compound L 116 NHC(O)O-t-butyl 117 NCH₃C(O)O-t-butyl 118 NHC(O)O-methyl119 NHC(O)O-phenyl 120 NHC(O)O-(S)-3-tetrahydrofuranyl 121NHC(O)O-2-picolinyl 122 NHC(O)O-(S)-5-oxazolidinonylmethyl 123NHC(O)O-4-carbomethoxyphenyl 124 NHC(O)O-isobutyl 125 NHC(O)O-allyl 126NHC(O)O-5-(1,3-dioxanyl) 127 NHC(O)O-4-acetamidophenyl 128NHC(O)O-2-furfuryl 129 NHC(O)O-2-thiofurfuryl 130 NHC(O)O-2-methoxyethyl131 NHC(O)O-4-tetrahydropyranyl 132 NHC(O)O-cyclohexyl 133NHC(O)O-cyclopentyl 134 NHC(O)O-2-hydroxyethyl 135NHC(O)O-cyclohexylmethyl 136 NHC(O)O-(R,S)-3-tetrahydrofuranyl 137NHC(O)O-3-pyridyl 138 NHC(O)O-benzyl 139 NHC(O)O-3-(tBOC-amino)propyl140 NHC(O)O-4-hydroxybutyl 141 NHC(O)O-5-hydroxypentyl 142NHC(O)O-(R,S)-2-pyranyl 143 NHC(O)O-3-(N-tBOC)-piperidinyl 144NHC(O)O-(R)-3-(2-oxo-4,4- dimethyl)furanyl 145NHC(O)O-3-methylthiopropyl 146 NHC(O)O-4-[(2,2-dimethyl)-1,3-dioxanyl]methyl 147 NHC(O)O-2-di-(hydroxymethyl)ethyl 148NHC(O)O-4-(N-tBOC)-piperidinylmethyl 149NHC(O)O-3-(N-tBOC)-piperidinylmethyl 150NHC(O)O-(dibenzyloxymethyl)methyl 151 NHC(O)O-di-(hydroxymethyl)methyl152 NHC(O)O-2-(N-tBOC)-piperidinylmethyl 153 NHC(O)O-3-piperidinyl-TFA154 NHC(O)O-(R,S)-(2- tetrahydropyranyl)methyl 155NHC(O)O-4-piperidinylmethyl-TFA 156NHC(O)O-(R,S)-tetrahydrofuranylmethyl 157 NHC(O)O-3-methylsulfonylpropyl158 NHC(O)O-3-piperidinylmethyl-TFA 159 NHC(O)O-2-piperidinylmethyl-TFA160 NHC(O)O-(R,S)-3-tetrahydrothiophenyl 161NHC(O)O-(R,S)-3-tetrahydrothiopyranyl 162 NHC(O)O-3-methoxypropyl

[0124] TABLE IIA

# Q¹ Q² B 28 3-methoxy 4-methoxy 3-methylphenyl 32 3-nitro H3-methylphenyl 33 4-cyano H 3-methylphenyl 34 3-methoxy 4-methoxy3-bromophenyl 35 3-methoxy 4-methoxy 2-methoxy-5- chlorophenyl 363-methoxy 4-methoxy 3-fluorophenyl 37 3-methoxy 4-methoxy 3-ethylphenyl38 3-methoxy 4-methoxy 3-methylthiophenyl 52 3-chloro 4-methoxy3-nitrophenyl 70 4-cyano 3-chloro 3-methylphenyl 87 1-imidazolyl H3-methylphenyl 90 3-hydroxymethyl 4-methoxy 3-methylphenyl 1033-(t-butoxycarbamoyl H 3-(t-butoxycarbamoyl methyl) methyl)phenyl

[0125] TABLE IIB

# Q₁ Q₃ 163 Cl N(Me)(Ac) 164 OMe N(Me)(Ac) 165 SMeCH₂NHC(O)O-(3s)-tetrahydrofuranyl 166 S(O)₂Me N(Me)(Ac) 167 OMeN(Me)(Ac) 168 SMe CH₂NHC(O)O-(3s)-tetrahydrofuranyl

[0126] The compounds of Table IIA correspond to compounds of formula(II) wherein one of said B components is phenyl with two substituents,Q¹ and Q². In accordance with formula (II):

[0127] Q¹ is selected from R¹, R², R⁴ or R⁵; and

[0128] Q² is selected from R¹ or R⁴.

[0129] The compounds of this invention may contain one or moreasymmetric carbon atoms and thus may occur as racemates and racemicmixtures, single enantiomers, diastereomeric mixtures and individualdiastereomers. All such isomeric forms of these compounds are expresslyincluded in the present invention. Each stereogenic carbon may be of theR or S configuration.

[0130] Combinations of substituents and variables envisioned by thisinvention are only those that result in the formation of stablecompounds. The term “stable”, as used herein, refers to compounds whichpossess stability sufficient to allow manufacture and which maintainsthe integrity of the compound for a sufficient period of time to beuseful for the purposes detailed herein (e.g., therapeutic orprophylactic administration to a mammal or for use in affinitychromatography applications). Typically, such compounds are stable at atemperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

[0131] As used herein, the compounds of this invention, including thecompounds of formulae I-IX, are defined to include pharmaceuticallyacceptable derivatives or prodrugs thereof. A “pharmaceuticallyacceptable derivative or prodrug” means any pharmaceutically acceptablesalt, ester, salt of an ester, or other derivative of a compound of thisinvention which, upon administration to a recipient, is capable ofproviding (directly or indirectly) a compound of this invention.Particularly favored derivatives and prodrugs are those that increasethe bioavailability of the compounds of this invention when suchcompounds are administered to a mammal (e.g., by allowing an orallyadministered compound to be more readily absorbed into the blood) orwhich enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies. Preferred prodrugs include derivatives where a group whichenhances aqueous solubility or active transport through the gut membraneis appended to the structure of formulae I-IX.

[0132] Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from pharmaceutically acceptableinorganic and organic acids and bases. Examples of suitable acid saltsinclude acetate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate,glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate,picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate,thiocyanate, tosylate and undecanoate. Other acids, such as oxalic,while not in themselves pharmaceutically acceptable, may be employed inthe preparation of salts useful as intermediates in obtaining thecompounds of the invention and their pharmaceutically acceptable acidaddition salts.

[0133] Salts derived from appropriate bases include alkali metal (e.g.,sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(C₁₋₄alkyl)₄ ⁺salts. This invention also envisions the quaternization of anybasic nitrogen-containing groups of the compounds disclosed herein.Water or oil-soluble or dispersible products may be obtained by suchquaternization.

[0134] The compounds of this invention may be synthesized usingconventional techniques. Advantageously, these compounds areconveniently synthesized from readily available starting materials.

[0135] In general, compounds of formula (I)-(IX) are convenientlyobtained via methods illustrated in General Synthetic Schemes 1-3.

[0136] In General Synthetic Scheme 1 (see below), an X-substitutedaniline is reacted with a Y-substituted phenylisocyanate under standardconditions to give the desired urea. In this process, X and Y may be oneor more independent substituents (or their suitably protected variants)as exemplified by the ring substituents listed for compounds of formulaeI-IX above, at any position on the aromatic ring.

[0137] In General Synthetic Scheme 2 (see above), a substitutedbenzaldehyde (here, 2-methoxy-4-nitro-substituted) is treatedsequentially with tosylmethylisocyanide, to give the resulting oxazole,then reduced by catalytic hydrogenation to give the desired aniline.Reaction of this aniline with an isocyanate (here, m-tolylisocyanate)under standard conditions gives the desired urea.

[0138] An alternate synthetic route is illustrated in General SyntheticScheme 3 (see above). A substituted benzaldehyde (here 4-nitrosubstituted) is converted to the corresponding oxazolyl aniline as shownin General Synthetic Scheme 2. This aniline is treated with asubstituted benzoic acid (here, 3-methyl-substituted) and a carboxylicacid activating agent, such as diphenylphosphoryl azide, under standardreaction conditions, to give the desired urea.

[0139] As can be appreciated by the skilled artisan, the above syntheticschemes are not intended to comprise a comprehensive list of all meansby which the compounds described and claimed in this application may besynthesized. Further methods will be evident to those of ordinary skillin the art. Additionally, the various synthetic steps described abovemay be performed in an alternate sequence or order to give the desiredcompounds.

[0140] The compounds of this invention may be modified by appendingappropriate functionalities to enhance selective biological properties.Such modifications are known in the art and include those which increasebiological penetration into a given biological compartment (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

[0141] The novel compounds of the present invention are excellentligands for IMPDH. Accordingly, these compounds are capable of targetingand inhibiting IMPDH enzyme. Inhibition can be measured by variousmethods, including, for example, IMP dehydrogenase HPLC assays(measuring enzymatic production of XMP and NADH from IMP and NAD) andIMP dehydrogenase spectrophotometric assays (measuring enzymaticproduction of NADH from NAD). [See C. Montero et al., Clinica ChimicaActa, 238, pp. 169-178 (1995)].

[0142] Pharmaceutical compositions of this invention comprise a compoundof formulae (I), (II) or (VII) or a pharmaceutically acceptable saltthereof; an additional agent selected from an immunosuppressant, ananti-cancer agent, an anti-viral agent, antiinflammatory agent,antifungal agent, antibiotic, or an anti-vascular hyperproliferationcompound; and any pharmaceutically acceptable carrier, adjuvant orvehicle. Alternate compositions of this invention comprise a compound offormulae (III)-(IX) or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable carrier, adjuvant or vehicle. Suchcomposition may optionally comprise an additional agent selected from animmunosuppressant, an anti-cancer agent, an anti-viral agent,antiinflammatory agent, antifungal agent, antibiotic, or ananti-vascular hyperproliferation compound.

[0143] The term “pharmaceutically acceptable carrier or adjuvant” refersto a carrier or adjuvant that may be administered to a patient, togetherwith a compound of this invention, and which does not destroy thepharmacological activity thereof and is nontoxic when administered indoses sufficient to deliver a therapeutic amount of the compound.

[0144] Pharmaceutically acceptable carriers, adjuvants and vehicles thatmay be used in the pharmaceutical compositions of this inventioninclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, self-emulsifying drug delivery systems (SEDDS) suchas dα-tocopherol polyethyleneglycol 1000 succinate, surfactants used inpharmaceutical dosage forms such as Tweens or other similar polymericdelivery matrices, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, orchemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of formulae I-IX.

[0145] The pharmaceutical compositions of this invention may beadministered orally, parenterally, by inhalation spray, topically,rectally, nasally, buccally, vaginally or via an implanted reservoir. Weprefer oral administration or administration by injection. Thepharmaceutical compositions of this invention may contain anyconventional non-toxic pharmaceutically-acceptable carriers, adjuvantsor vehicles. In some cases, the pH of the formulation may be adjustedwith pharmaceutically acceptable acids, bases or buffers to enhance thestability of the formulated compound or its delivery form. The termparenteral as used herein includes subcutaneous, intracutaneous,intravenous, intramuscular, intraarticular, intraarterial,intrasynovial, intrasternal, intrathecal, intralesional and intracranialinjection or infusion techniques.

[0146] The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example, as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according totechniques known in the art using suitable dispersing or wetting agents(such as, for example, Tween 80) and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are mannitol, water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose, any bland fixed oil may be employed includingsynthetic mono- or diglycerides. Fatty acids, such as oleic acid and itsglyceride derivatives are useful in the preparation of injectables, asare natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant such as those described in Pharmacopeia Helvetica, Ph.Helv., or a similar alcohol, or carboxymethyl celluose or similardispersing agents which are commonly used in the formulation ofpharmaceutically acceptable dosage forms such as emulsions and orsuspensions Other commonly used surfactants such as Tweens or Spansand/or other similar emulsifying agents or bioavailability enhancerswhich are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

[0147] The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, emulsions and aqueous suspensions,dispersions and solutions. In the case of tablets for oral use, carrierswhich are commonly used include lactose and corn starch. Lubricatingagents, such as magnesium stearate, are also typically added. For oraladministration in a capsule form, useful diluents include lactose anddried corn starch. When aqueous suspensions and/or emulsions areadministered orally, the active ingredient may be suspended or dissolvedin an oily phase is combined with emulsifying and/or suspending agents.If desired, certain sweetening and/or flavoring and/or coloring agentsmay be added.

[0148] The pharmaceutical compositions of this invention may also beadministered in the form of suppositories for rectal administration.These compositions can be prepared by mixing a compound of thisinvention with a suitable non-irritating excipient which is solid atroom temperature but liquid at the rectal temperature and therefore willmelt in the rectum to release the active components. Such materialsinclude, but are not limited to, cocoa butter, beeswax and polyethyleneglycols.

[0149] Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For applicationtopically to the skin, the pharmaceutical composition should beformulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier with suitable emulsifying agents. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water. The pharmaceuticalcompositions of this invention may also be topically applied to thelower intestinal tract by rectal suppository formulation or in asuitable enema formulation. Topically-transdermal patches are alsoincluded in this invention.

[0150] The pharmaceutical compositions of this invention may beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other solubilizing or dispersingagents known in the art.

[0151] Dosage levels of between about 0.01 and about 100 mg/kg bodyweight per day, preferably between about 0.5 and about 75 mg/kg bodyweight per day of the IMPDH inhibitory compounds described herein areuseful in a monotherapy and/or in combination therapy for the preventionand treatment of IMPDH mediated disease. Typically, the pharmaceuticalcompositions of this invention will be administered from about 1 toabout 5 times per day or alternatively, as a continuous infusion. Suchadministration can be used as a chronic or acute therapy. The amount ofactive ingredient that may be combined with the carrier materials toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Preferably,such preparations contain from about 20% to about 80% active compound.

[0152] When the compositions of this invention comprise a combination ofan IMPDH inhibitor of formulae (I)-(IX) and one or more additionaltherapeutic or prophylactic agents, both the IMPDH inhibitor and theadditional agent should be present at dosage levels of between about 10to 100%, and more preferably between about 10 to 80% of the dosagenormally administered in a monotherapy regimen. The additional agentsmay be administered separately, as part of a multiple dose regimen, fromthe compounds of this invention. Alternatively, those agents may be partof a single dosage form, mixed together with the compounds of thisinvention in a single composition.

[0153] According to one embodiment, the pharmaceutical compositions ofthis invention comprise an additional immunosuppression agent. Examplesof additional immunosuppression agents include, but are not limited to,cyclosporin A, FK506,rapamycin, leflunomide, deoxyspergualin,prednisone, azathioprine, mycophenolate mofetil, OKT3,ATAG, interferonand mizoribine.

[0154] According to an alternate embodiment, the pharmaceuticalcompositions of this invention may additionally comprise an anti-canceragent. Examples of anti-cancer agents include, but are not limited to,cis-platin, actinomycin D, doxorubicin, vincristine, vinblastine,etoposide, amsacrine, mitoxantrone, tenipaside, taxol, colchicine,cyclosporin A, phenothiazines, interferon and thioxantheres.

[0155] According to another alternate embodiment, the pharmaceuticalcompositions of this invention may additionally comprise an anti-viralagent. Examples of anti-viral agents include, but are not limited to,Cytovene, Ganciclovir, trisodium phosphonoformate, Ribavirin, d4T, ddI,AZT, and acyclovir.

[0156] According to yet another alternate embodiment, the pharmaceuticalcompositions of this invention may additionally comprise ananti-vascular hyperproliferative agent. Examples of anti-vascularhyperproliferative agents include, but are not limited to, HMG Co-Areductase inhibitors such as lovastatin, thromboxane A2 synthetaseinhibitors, eicosapentanoic acid, ciprostene, trapidil, ACE inhibitors,low molecular weight heparin, mycophenolic acid, rapamycin and5-(3′-pyridinylmethyl)benzofuran-2-carboxylate.

[0157] Upon improvement of a patient's condition, a maintenance dose ofa compound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease.Patients may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

[0158] As the skilled artisan will appreciate, lower or higher dosesthan those recited above may be required. Specific dosage and treatmentregimens for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health status, sex, diet, time ofadministration, rate of excretion, drug combination, the severity andcourse of the infection, the patient's disposition to the infection andthe judgment of the treating physician.

[0159] In an alternate embodiment, this invention provides methods oftreating or preventing IMPDH mediated disease in a a mammal comprisingthe step of administrating to said mammal any of the pharmaceuticalcompositions and combinations described above. If the pharmaceuticalcomposition only comprises the IMPDH inhibitor of this invention as theactive component, such methods may additionally comprise the step ofadministering to said mammal an agent selected from an antiinflammatoryagent, immunosuppressant, an anti-cancer agent, an anti-viral agent, oran anti-vascular hyperproliferation compound. Such additional agent maybe administered to the mammal prior to, concurrently with, or followingthe administration of the IMPDH inhibitor composition.

[0160] In a preferred embodiment, these methods are useful insuppressing an immune response in a mammal. Such methods are useful intreating or preventing diseases, including, transplant rejection (e.g.,kidney, liver, heart, lung, pancreas (islet cells), bone marrow, cornea,small bowel and skin allografts and heart valve xenografts), graftversus host disease, and autoimmune diseases, such as rheumatoidarthritis, multiple sclerosis, juvenile diabetes, asthma, inflammatorybowel disease (Crohn's disease, ulcerative colitus), lupus, diabetes,mellitus myasthenia gravis, psoriasis, dermatitis, eczema, seborrhoea,pulmonary inflammation, eye uveitis, hepatitis, Grave's disease,Hashimoto's thyroiditis, Behcet's or Sjorgen's syndrome (dryeyes/mouth), pernicious or immunohaemolytic anaemia, idiopathic adrenalinsufficiency, polyglandular autoimmune syndrome, glomerulonephritis,scleroderma, lichen planus, viteligo (depigmentation of the skin),autoimmune thyroiditis, and alveolitis.

[0161] These methods comprise the step of administering to the mammal acomposition comprising a compound of any of formulae I-IX and apharmaceutically acceptable adjuvant. In a preferred embodiment, thisparticular method comprises the additional step of administering to saidmammal a composition comprising an additional immunosuppressant and apharmaceutically acceptable adjuvant.

[0162] Alternatively, this method comprises the step of administering tosaid mammal a composition comprising a compound of formulae I-IX; anadditional immunosuppressive agent and a pharmaceutically acceptableadjuvant.

[0163] In an alternate preferred embodiment, these methods are usefulfor inhibiting viral replication in a mammal. Such methods are useful intreating or preventing, DNA and RNA viral diseases caused by, forexample, HTLV-1 and HTLV-2, HIV-1 and HIV-2, nasopharyngeal carcinomavirus, HBV, HCV, HGV, yellow fever virus, dengue fever virus, Japaneseencephalitis virus, human papilloma virus, rhinoviruses and Herpesviruses, such as Epstein-Barr, cytomegaloviruses and Herpes Simplex,Types 1 and 2,or Type 6. [See, U.S. Pat. No. 5,380,879].

[0164] These methods comprise the step of administering to the mammal acomposition comprising a compound of any of formulae I-IX, and apharmaceutically acceptable adjuvant. In a preferred embodiment, thisparticular method comprises the additional step of administering to saidmammal a composition comprising an additional anti-viral agent and apharmaceutically acceptable adjuvant.

[0165] Alternatively, this method comprises the step of administering tosaid mammal a composition comprising a compound of formulae I-IX; anadditional anti-viral agent and a pharmaceutically acceptable adjuvant.

[0166] In another alternate preferred embodiment, these methods areuseful for inhibiting vascular cellular hyperproliferation in a mammal.Such methods are useful in treating or preventing diseases, including,restenosis, stenosis, artherosclerosis and other hyperproliferativevascular disease.

[0167] These methods comprise the step of administering to the mammal acomposition comprising a compound of any of formulae I-IX, and apharmaceutically acceptable adjuvant. In a preferred embodiment, thisparticular method comprises the additional step of administering to saidmammal a composition comprising an additional anti-vascularhyperproliferative agent and a pharmaceutically acceptable adjuvant.

[0168] Alternatively, this method comprises the step of administering tosaid mammal a composition comprising a compound of formulae I-IX; anadditional anti-vascular hyperproliferative agent and a pharmaceuticallyacceptable adjuvant.

[0169] In another alternate preferred embodiment, these methods areuseful for inhibiting tumors and cancer in a mammal. Such methods areuseful in treating or preventing diseases, including, tumors andmalignancies, such as lymphoma, leukemia and other forms of cancer.

[0170] These methods comprise the step of administering to the mammal acomposition comprising a compound of any of formulae I-IX, and apharmaceutically acceptable adjuvant. In a preferred embodiment, thisparticular method comprises the additional step of administering to saidmammal a composition comprising an additional anti-tumor or anti-canceragent and a pharmaceutically acceptable adjuvant.

[0171] Alternatively, this method comprises the step of administering tosaid mammal a composition comprising a compound of formulae I-IX; anadditional anti-tumor or anti-cancer agent and a pharmaceuticallyacceptable adjuvant.

[0172] In another alternate preferred embodiment, these methods areuseful for inhibiting inflammation and inflammatory diseases in amammal. Such methods are useful in treating or preventing diseases,including, osteoarthritis, acute pancreatitis, chronic pancreatitis,asthma and adult respiratory distress syndrome.

[0173] These methods comprise the step of administering to the mammal acomposition comprising a compound of any of formulae I-IX, and apharmaceutically acceptable adjuvant. In a preferred embodiment, thisparticular method comprises the additional step of administering to saidmammal a composition comprising an antiinflammatory agent and apharmaceutically acceptable adjuvant.

[0174] In order that this invention be more fully understood, thefollowing examples are set forth. These examples are for the purpose ofillustration only and are not to be construed as limiting the scope ofthe invention in any way.

[0175] General Materials and Methods

[0176] All temperatures are recorded in degrees Celsius. Thin layerchromatography (TLC) was carried out using 0.25 mm thick E. Merck silicagel 60 F₂₅₄ plates and elution with the indicated solvent system.Detection of the compounds was carried out by treating the plate with anappropriate visualizing agent, such as 10% solution of phosphomolybdicacid in ethanol or a 0.1% solution of ninhydrin in ethanol, followed byheating, and/or by exposure to UV light or iodine vapors whenappropriate. Analytical HPLC was carried out using a RaininMycrosorb-MV, 5μ Cyano reverse phase column, 3.9mm ×150mm, with a flowrate of 1.0 mL/minute and a solvent gradient of 5-100% acetonitrile(0.1% TFA) in water (0.1% TFA). HPLC retention times were recorded inminutes. NMR spectral data was acquired using a Bruker AMX500 in theindicated solvent.

[0177] The IMP dehydrogenase HPLC assay follows our standard conditionsfor the enzymatic production of XMP and NADH from IMP and NAD, bututilizes high pressure liquid chromatography on a C18 column with ionpairing reagents to separate all four components. The extent of reactionis then determined from the resulting product peak areas. This assay isparticularly useful for determining the inhibition profiles of compoundswhich have significant absorbance in the UV-visible region between 290and 340 nM.

[0178] The reaction mixture typically contains 0.1 M KPi; pH 8.0, 0.1MKCl, 0.5 mM EDTA, 2 mM DTT, and 0.2 mM each of IMP and NAD. Thissolution is incubated at 37° C. for 10 minutes. The reaction is startedby the addition of enzyme to a final concentration of 20 to 100 nM, andis allowed to proceed for 10 minutes. After the allotted time, thereaction is quenched by the addition of mycophenolic acid to a finalconcentration of 0.01 mM.

[0179] The extent of conversion is monitored by HPLC using a RaininMicrosorb ODS column C18-200 of

[0180] To a solution of glacial acetic acid (46 mL), acetic anhydride(46 mL, 485 mmole) and 2-chloro-4-nitrotoluene (5 g, 29.1 mmole) at 0°C. was added conc. H₂SO₄ (6.9 mL) in a dropwise fashion. Upon completeaddition, CrO₃ (8.08 g, 80.8 mmole) was added portion-wise over 60 mins.Following an additional 15 mins of stirring at 0° C., the reactionmixture was poured over ice and the resulting precipitate was isolatedby filtration, rinsing with cold H₂O. Purification by flashchromatography, eluting with a gradient of 15-50% EtOAc in hexanes,provided 2.02 g (24%, 40% based on recovered starting material) B1 as awhite solid. The ¹H NMR was consistent with that of the desiredstructure.

[0181] Compound B1 was dissolved in 1:1 ethanol/water (20 mL), treatedwith conc. H₂SO₄ (2 mL) and refluxed for 1 hour. Upon cooling to ambienttemperature, the reaction was extracted 3×'s with diethyl ether. Theethereal solution was washed twice with water, dried over Na₂SO₄ andconcentrated in vacvo to yield a yellow solid. Purified product wasobtained through two recrystallizations from hot Et₂0 /hexanes, yielding620 mg (47.6%) B2 as a lightly yellowed crystalline solid. The ¹H NMRwas consistent with that of the desired structure.

[0182] A mixture of B2 (200 mg, 1.2 mmol), tosylmethyl isocyanide (236mg, 1.2 mmol), and powdered K₂CO₃ (172 mg, 1.2 mmole) in methanol (13mL) was heated at reflux for 90 minutes and then stirred overnight atambient temperature. Upon concentration to dryness, the mixture waspartitioned between CH₂Cl₂ and water. The organics were separated,washed with 0.5N HCl, water and brine and then dried over Na₂SO₄. Thesolvent was removed in vacuo to provide a crude yellow solid. Purifiedproduct B3 was obtained through flash chromatography, eluting with agradient of 0-2.5% CH₃ OH in CH₂Cl₂, and recrystallization(CH₂Cl₂/hexanes) in a yield of 3.3 g (68%) as a light yellow crystallinesolid. The ¹H NMR was consistent with that of the desired structure.

[0183] A solution of B3 (150 mg, 0.67 mmole) in ethanol (7.5 mL) wastreated with SnCl₂.2H₂O (excess; ca. 5 equivalents) and heated at refluxfor 30 minutes. The mixture was cooled to ambient temperature, dilutedwith diethyl ether and partitioned with 2N NaOH. The organics wereseparated, washed with water and brine, dried over Na₂SO₄ andconcentrated in vacuo. Purified product B4 was obtained through flashchromatography, eluting with a gradient of 0-0.5% CH₃OH in CH₂Cl₂,in ayield of 54 mg (41.5%) as a light yellow oil. The ¹H NMR was consistentwith that of the desired structure.

[0184] To a solution of 20 mg (103 μmole) B4 in 1 mL CH₂Cl₂ was added 20μL m-tolylisocyanate at ambient temperature. After stirring overnight,43 was isolated in pure form by filtration with an EtOAc/hexanes rinsein a yield of 25 mg (74%). ¹H NMR (500 MHz, d₆-DMSO) δ9.06 (s), 8.73(s), 8.50 (s), 7.89 (s), 7.73 (d), 7.67 (s), 7.42 (d), 7.31 (s), 7.23(d), 7.18 (t), 6.82 (d), 2.27 (s). R_(f) 0.28 (5% MeOH/CH₂Cl₂).

EXAMPLE 3 Synthesis of Compound 56

[0185]

[0186] C1(8.14 g, 51%) was prepared from 2-methyl-5-nitroanisole (10.0g, 60 mmole) in a fashion directly analogous to the preparation of B1 asdescribed above. The ¹H NMR was consistent with that of the desiredstructure.

[0187] A stirred suspension of C1 (81.94 g, 307 mmole) in dioxane (100mL) was treated with concentrated HCl (20 mL) and heated at refluxovernight. Upon cooling to ambient temperature, the product C2precipitated as a light yellow crystalline solid in a yield of 40.65 g(73.1%). The filtrate was concentrated to a volume of ca. 80 mL and asecond crop of product crystals was driven from solution by the additionof hexanes, yielding 8.91 g (16.0%). Both batches were identical by ¹HNMR and TLC analysis and were consistent with that of the desiredmaterial. The total yield of C2 was 49.56 g (89.1%).

[0188] A solution of C2 (456 mg, 2.51 mmole), tosylmethyl isocyanide(490 mg, 2.51 mmole) and K₂CO₃ (347 mg, 251 mmole) were dissolved inmethanol and heated to reflux for 1.5 hours. The product mixture wasthen concentrated in vacuo, redissolved in CH₂Cl₂, washed with water andbrine, dried over Na₂SO₄ and again concentrated in vacuo. Purifiedproduct C3 was obtained through recrystallization (Et₂O/hexanes) toyield 375 mg (68%). The ¹H NMR was consistent with that of the desiredstructure.

[0189] A solution of C3 (4.214 g, 19.1 mmole) in EtOAc (150 mL) wastreated with 10%Pd/C (1.05 g, 25 wt. % of C3) and subjected to 40 psi H₂(g) (Parr Hydrogenation Apparatus) overnight. The reaction mixture wasfiltered and concentrated in vacuo. Pure product C4 was obtained throughflash chromatography, eluting with a gradient of 30-40% EtOAc/hexanes,in a yield of 3.4 g (93%). The ¹H NMR was consistent with that of thedesired structure.

[0190] To a solution of C4 (25 mg, 0.131 mmole) in CH₂Cl₂ (1 mL) wasadded toll isocyanate (25 μL, 0.197 mmole) at ambient temperature. Afterstirring overnight, 56 was isolated in pure form by filtration with aCH₂Cl₂ rinse in a yield of 42 mg (74%). ¹H NMR (500 MHz, d₆-DMSO) 6 8.87(s), 8.64 (s), 8.37 (s), 7.60 (d), 7.46 (d), 7.42 (s), 7.33 (s), 7.23(d), 7.16-7.19 (t), 7.05 (dd), 6.80 (d), 3.92 (s), 2.28 (s). R_(f) 0.46(5% MeOH/CH₂Cl₂).

EXAMPLE 4 Synthesis of Compound 59

[0191]

[0192] To a solution of C4 (75 mg, 0.394 mmole) in dichloroethane (5 mL)was added 3-nitrophenyl isocyanate (97 mg, 0.591 mmole) at ambienttemperature. After stirring overnight, D1 was isolated in pure form byfiltration with a CH₂Cl₂ rinse in a yield of 110.3 mg (79%). The ¹H NMRwas consistent with that of the desired structure.

[0193] To a stirred suspension of D1 (95 mg, 0.268 mmole) in EtOH (20mL) was added SnCl₂.2H₂O (302 mg, 1.34 mmole). The reaction mixture wasbrought to reflux, at which time dissolution occurred, for 1.5 hours.The solution was cooled to ambient temperature, diluted with EtOAc,washed with 2N NaOH and brine, dried (Na₂SO₄) and concentrated in vacuo.Pure product 59 was obtained through flash chromatography (eluting witha gradient of 2.5-5% MeOH in CH₂Cl₂), followed by selectivecrystallization of the desired material from slightly impure fractionsin a yield of 15.7 mg (18%).

[0194]¹H NMR (500 MHz, d₆-DMSO) δ8.83 (s), 8.44 (s), 8.35 (s), 7.59 (d),7.48 (d), 7.40 (s), 6.97-7.04 (dd), 6.86-6.92 (t), 6.83 (d), 6.54 (dd),6.20 (dd), 5.05 (br s), 3.92 (s). R_(f)0.20 (5% MeOH/CH₂Cl₂)

EXAMPLE 5 Synthesis of Compound 113

[0195]

[0196] A solution of 3-aminobenzylamine (826 mg, 6.87 mmole) andtriethylamine (2.39 mL, 17.18 mmole) was treated withdi-t-butyldicarbonate (1.50 g, 6.87 mmole) and the mixture was stirredat ambient temperature for 2 hours. The reaction was then diluted withCH₂Cl₂, washed with NaHCO₃(aq), water and brine, dried (Na₂SO₄) andconcentrated in vacuo. Pure E1 was obtained by flash chromatography,eluting with 25% EtOAc in hexanes in a yield of 200 mg (46%). The ¹H NMRwas consistent with that of the desired structure.

[0197] A solution of C4 (150 mg, 0.789 mmole) and1,1-dicarbonylimidiazole (160 mg, 0.986 mmole) were combined in THF (5mL) and stirred for 6 hours at ambient temperature. The precipitation ofimidazole was noted. To this was then added El (351 mg, 1.58 mmole) andN,N-dimethylaminopyridine (97 mg, 0.789 mmole) and the mixture wasrefluxed overnight, resulting in a homogenous solution. Upon cooling toambient temperature, the reaction was diluted with EtOAc (20 mL), washedwith KHSO₄(aq), water, and brine, dried (MgSO₄) and concentrated. Pure113 was obtained through flash chromatography, eluting with a gradientof 20-30-35% acetone in hexanes in a yield of 164 mg (47%). ¹H NMR (500MHz, d₆-DMSO) 6 8.90 (s), 8.75 (s), 8.38 (s), 7.60 (d), 7.51 (s),7.3-7.46 (m), 7.21-7.27 (t), 7.05 (dd), 6.87 (d), 4.12 (d), 3.93 (s),1.44 (s). R_(f)0.21 (5% MeOH/CH₂Cl₂)

EXAMPLE 6 Synthesis of Compound 70

[0198]

[0199] A solution of 3-chloro-4-cyanoaniline (500 mg, 7.76 mmole) andm-tolylisocyanate (1.0 mL, 3.17 mmole) in CH₂Cl₂ (3 mL) was stirredovernight at ambient temperature. The reaction mixture was concentratedand pure 70 was obtained through MPLC, eluting with 1% MeOH in CH₂Cl₂,in a yield of 285 mg (31%). ¹H NMR (500 MHz, d₆-DMSO) δ9.36 (s), 8.88(s), 7.94 (s), 7.83 (d), 7.44 (d), 7.30 (s), 7.24 (d), 7.15-7.20 (t),6.82 (d), 2.29 (s). R_(f) 0.36 (5% MeOH/CH₂Cl₂)

EXAMPLE 7 Synthesis of Compound 108

[0200]

[0201] To a solution of 3,4,5-trimethoxyacetophenone (9.2 g, 43.4 mmol)in pyridine (35 mL) was added selenium dioxide (6.3 g, 56.7 mmol) andthe resulting solution was heated at reflux overnight. The reactionmixture was cooled to ambient temperature, filtered through celite andconcentrated to yield a dark brown oil which was dissolved into ethylacetate and washed with 1.0 N HCl and then with saturated NaHCO₃. Thebasic aqueous layer was diluted with ether and acidified withconcentrated HCl. The layers were separated and the organic phase waswashed with brine and then dried (Na₂SO₄) to give 8.4 g of a dark yellowsolid. Recrystallization of this material from ethyl acetate-hexane thengave G1 (6.8 g) as a pale yellow solid. The ¹H NMR was consistent withthat of the desired structure.

[0202] A mixture of 59 (64 mg, 0.20 mmole), G1 (300 mg, 1.20 mmole) andEDC (300 mg, 1.6 mmole) in THF (5 mL) was stirred overnight at ambienttemperature. The reaction was diluted with EtOAc (150 mL), washed withwater, dried (MgSO₄) and concentrated in vacuo. Pure 108 was obtainedthrough MPLC, eluting with a gradient system of 0-1%MeOH in CH₂Cl₂, in ayield of 37.4 mg (35%).

[0203]¹H NMR (500 MHz, d₆-DMSO) δ9.83 (s), 8.23 (s), 8.18 (s), 7.65 (s),7.61 (s), 7.35 (d), 7.33 (s), 7.29 (s), 7.27 (s), 7.11 (s), 7.06-7.10(t), 6.94-6.99 (t), 6.52 (d)3.68 (s), 3.63 (s), 3.61 (s). R_(f) 0.26 (5%MeOH/CH₂Cl₂).

EXAMPLE 8 Synthesis of Compound 115

[0204]

[0205] A solution of 59 (300 mg, 1.58 mmole) and m-toll isothiocyanate(2.0 mL, 14.7 mmole) in CH₂Cl₂ (5 mL) was stirred at ambient temperatureovernight. To drive the reaction to completion, additional m-tollisothiocyanate (1.0 mL, 7.4 mmole) was added and the mixture was heatedto reflux for 3 hours. The reaction was concentrated in vacuo and 115was obtained in pure form through MPLC, eluting with 0-5% EtOAc inCH₂Cl₂, in a yield of 210 mg (39%). ¹H NMR (500 MHz, d₆-DMSO) δ7.90 (s),7.89 (s), 7.82 (s), 7.75 (d), 7.64 (s) 7.44 (s), 7.32-7.37 (t), 7.27(s), 7.13-7.21 (m), 6.91 (dd), 3.98 (s), 2.40 (s). R_(f) 0.36 (5%MeOH/CH₂Cl₂).

EXAMPLE 9 Synthesis of Compound 97

[0206]

[0207] A solution of nitroaniline (1.0 g, 7.13 mmole) in CH₂Cl₂ (25 mL)was treated with pyridine (2.9 mL, 36 mmole) and trifluoroaceticanhydride (5 mL, 36 mmole) and stirred at ambient temperature for 3hours. The reaction was diluted further with CH₂Cl₂, washed with 1N HCland brine, dried (MgSO₄) and concentrated in vacuo to yield I1 (1.61 g,95%) as a white solid. The ¹H NMR was consistent with that of thedesired structure.

[0208] To a slurry of NaH (60% oil dispersion; 34 mg, 1.42 mmole) in THF(10 mL) at 0° C. was added a solution of I1 (200 mg, 0.85 mmole) in THF(10 mL) and the mixture stirred for 1 hour. To this was added methyliodide (100 μL, 1.7 mmole) and the mixture was stirred overnight atambient temperature. The reaction was poured into water and extractedwith EtOAc. The organics were separated, dried (MgSO₄) and concentratedin vacuo. Pure I2 was obtained through flash chromatography, elutingwith 5% EtOAc in hexanes, in a yield of 163 mg (66%) as a yellow solid.The ¹H NMR was consistent with that of the desired structure.

[0209] A solution of I2 (163 mg, 0.66 mmole) in ethanol (5 mL) wastreated with Pd/C (20 mg) and subjected to H₂ (1 atm.) for 3 hours. Thereaction was filtered and concentrated in vacuo to yield I3 (120 mg,84%) as a waxy solid. The ¹H NMR was consistent with that of the desiredstructure.

[0210] To a solution of triphosgene (31 mg, 0.104 mmole) indichloroethane (1 mL) was added in a dropwise fashion a solution of B4(50 mg, 0.260 mmole) and diisopropylethylamine (67 mg, 518 mmole) indichloroethane (5 mL). The reaction mixture was stirred for anadditional 1 hour at ambient temperature, treated with I3 (50 mg, 0.230mmole) and stirred overnight. The entire reaction mixture was subjectedto flash chromatography, eluting with 1% MeOH in CH₂Cl₂, to provide pure97 in a yield of 8 mg (7%). ¹H NMR (500 MHz, d₆-DMSO) δ9.20 (s), 8.98(s), 8.39 (s), 7.67 (s), 7.63 (d), 7.48 (s), 7.38-7.45 (m), 7.04-7.10(t), 3.95 (s), 3.31 (s). R_(f) 0.37 (5% MeOH/CH₂Cl₂).

EXAMPLE 10 Synthesis of Compound 111

[0211]

[0212] A solution of 59(50 mg, 0.154 mmole) and triethylamine (31 mg,0.308 mmole) in DMF (0.5 mL) was treated in a dropwise fashion withphenylacetyl chloride (25 mg, 0.169 mmole) and the reaction stirredovernight at ambient temperature. The mixture was diluted with CH₂Cl₂,washed with NaHCO₃(aq) and water, dried over MgSO₄ and concentrated invacuo. Pure 111 was isolated by flash chromatography, eluting with 2%MeOH in CH₂Cl₂,in a yield of 42 mg (62%). ¹H NMR (500 MHz, d₆-DMSO)δ10.20 (s), 8.90 (s), 8.79 (s), 8.39 (s), 7.88 (s), 7.63 (d), 7.53 (d),7.44 (s), 7.25-7.40 (m), 7.22 (t), 7.14 (d), 7.05 (dd), 3.96 (s), 3.66(s). R_(f) 0.31 (5% MeOH/CH₂Cl₂).

EXAMPLE 11 Synthesis of Compound 102

[0213]

[0214] A solution of 2-methyl-5-nitrobenzoic acid (15 g, 82.8 mmole) inDMF (75 mL) was treated with methyl iodide (6.7 mL, 107.64 mmole)followed by powdered K₂CO₃ (17.2 g, 124.2 mmole) (extreme exotherm) andthe suspension stirred at ambient temperature overnight. The reactionmixture was partitioned between EtOAc and water, the organics separatedand washed with water and brine, dried (Na₂SO₄) and concentrated invacuo to yield K1 (15.86 g, 98%) in pure form as an off-white solid. The¹H NMR was consistent with that of the desired structure.

[0215] K2 (4.09 g, 16.2%) was prepared from K1 (15.86 g, 81.3 mmole) ina fashion analogous to the preparation of B1 as described above. The ¹HNMR was consistent with that of the desired structure.

[0216] A solution of K2 (2.5 g, 8.03 mmole) in dioxane (10 mL) wastreated with conc. HCl (0.5 mL) and the mixture was heated to reflux for2 hours. Additional conc. HCl (0.5 mL) was added and the reactionrefluxed for 3 hours longer. The mixture was diluted with EtOAc, washedwith water and brine, dried (Na₂SO₄) and concentrated in vacuo. Pure K3was obtained through flash chromatography, eluting with a gradient of20-30- 50% Et₂O in hexanes, in a yield of 1.14 g (68%). Also isolatedwas 215 mg (11.8%) of the hydrated aldehyde. The ¹H NMRs were consistentwith that of the desired structures.

[0217] A solution of K3 (300 mg, 1.43 mmole) in benzene (5 mL) wastreated with 1,3-propane diol (114 μL, 1.573 mmole) and p-TsOH.H₂O (27mg, 0.14 mmole) and the mixture was refluxed with Dean-Stark removal ofwater for 4.5 hours. The reaction was cooled to ambient temperature,partitioned between EtOAc and dilute NaHCO₃, the organics separated,washed with brine, dried (Na₂SO₄) and concentrated in vacuo. Pure K4 wasobtained through flash chromatography, eluting with a gradient of 20-25%Et₂O in hexanes, in a yield of 324 mg (84.5%) as an off-whitecrystalline solid. The ¹H NMR was consistent with that of the desiredstructure.

[0218] A solution of K4 (289 mg, 1.08 mmole) in THF (5 mL) at 0° C. wastreated dropwise with a solution of DIBAL (1.0M in CH₂Cl₂; 2.7 mL, 2.7mmole) and stirred for 40 minutes. The reaction was quenched by additionof saturated Rochelle's salt solution (10 mL), diluted with EtOAc andstirred for 30 minutes. The organics were collected, washed with brine,dried (Na₂SO₄) and concentrated in vacuo to give 250 mg (97%) of K5 as awhite crystalline solid. The ¹H NMR was consistent with that of thedesired structure.

[0219] A solution of K5 (250 mg, 1.05 mmole) in CH₂Cl₂ (4 mL) at 0° C.was treated with pyridine (110 μL, 1.37 mmole), benzoyl chloride (146μL, 1.26 mmole) and 4-DMAP (catalytic), and stirred at ambienttemperature overnight. The reaction mixture was diluted with CH₂Cl₂,washed with 0.5N HCl, water and brine, dried (Na₂SO₄) and concentratedin vacuo. Pure K6 was obtained through flash chromatography, elutingwith 10% EtOAc in hexanes, in a yield of 340 mg (99%) as a white solid.The ¹H NMR was consistent with that of the desired structure.

[0220] A solution of K6 (326 mg, 0.99 mmole) in dioxane (7 mL) wastreated with 2.0N HCl (5 mL) and the mixture heated at 80° C. overnight.The reaction mixture was diluted with EtOAc and washed with saturatedNaHCO₃(aq), water and brine, dried (Na₂SO₄) and concentrated in vacuo.Pure K7 was obtained through flash chromatography, eluting with 30% Et₂Oin hexanes, in a yield of 208 mg (77.5%) as a white solid. The ¹H NMRwas consistent with that of the desired structure.

[0221] A solution of K7 (208 mg, 0.729 mmole) in MeOH (6 mL) was treatedwith K₂CO₃ (101 mg, 0.765 mmole) and TosMIC (149 mg, 0.765 mmole) andthe solution heated at 60° C. for one hour. The reaction wasconcentrated in vacuo, redissolved in CH₂Cl₂ and washed with 1.0N NaOH(diluted with saturated NaHCO₃). The aqueous portion was back-extractedwith CH₂Cl₂,the organics combined and washed with water and brine, dried(Na₂SO₄) and concentrated in vacuo. Pure K8 was obtained through flashchromatography, eluting with a gradient of 10-50% acetone in hexanes, ina yield of 70 mg (44%). The ¹H NMR was consistent with that of thedesired structure.

[0222] A solution of K8 (70 mg, 0.318) in acetic anhydride (1.5 mL) andpyridine (1.0 mL) was treated with 4-DMAP (catalytic) and stirred atambient temperature for 3 hours. The mixture was diluted with CH₂Cl₂,washed with 1.0N HCl, water and brine, dried (Na₂SO₄) and concentratedin vacuo to provide K9 in a yield of 82 mg (98%) as a pale yellow solid.The ¹H NMR was consistent with that of the desired structure.

[0223] A solution of K9 (80 mg, 0.305 mmole) in dry EtOH (4mL) wastreated with SnCl₂. 2H₂O (241 mg, 1.07 mmole) and the mixture heated at60° C. for 50 minutes. The reaction was diluted with EtOAc, washed withsaturated NaHCO₃, water and brine, dried (Na₂SO₄) and concentrated invacuo. Pure K10 was obtained through flash chromatography, eluting witha gradient of 20-30% acetone in hexanes, in a yield of 52 mg (73.4%) asa pale yellow oil. The ¹H NMR was consistent with that of the desiredstructure.

[0224] A solution of K10 (52 mg, 0.224 mmole) in dichloroethane (2 mL)was treated with m-tolyl isocyanate (43 μL, 0.336 mmole) and stirredovernight at ambient temperature. The mixture was diluted withCH₂Cl₂:hexanes (2:1), filtered and rinsed with the same solvent systemto provide K11 (67 mg, 82%) as a white solid. The ¹H NMR was consistentwith that of the desired structure.

[0225] A solution of K11 (33 mg, 0.09 mmole) in MeOH (2 mL) was treatedwith 1.0N NaOH (135 μL, 0.135 mmole) and stirred at ambient temperaturefor 1.5 hours. The reaction was neutralized by addition of 1.0N HCl (135μL) and concentrated in vacuo. The white solid was rinsed with water andCH₂Cl₂:hexanes (2:1) and dried in vacuo to provide 102 (20 mg, 68%) as awhite solid. ¹H NMR (500 MHz, d₆-DMSO) δ9.29 (s), 9.00 (s), 8.42 (s),7.69 (s), 7.55 (m), 7.37 (s), 7.33 (s), 7.27 (d), 7.16 (t), 6.80 (d),5.39 (t), 4.58 (s), 2.28 (s). R_(f) 0.13 (1:1 hexanes/acetone).

EXAMPLE 12 Synthesis of Compound 106

[0226]

[0227] A solution of C4 (50 mg, 0.263 mmole) in THF (2 mL) was treatedwith CDI (53 mg, 0.330 mmole) and stirred at ambient temperature for 4hours. To this was added 1-acetyl-6-aminoindole (93 mg, 0.526 mmole,Sigma Chemical Co.) and 4-DMAP (35 mg, 0.289 mmole) and the mixturerefluxed overnight. Diluted with EtOAc (100 mL), washed with 5% KHSO₄,water and brine, dried (Na₂SO₄) and concentrated in vacuo. Redissolvedin EtOAc and filtered to removed insoluble materials and reconcentratedin vacuo. Pure 106 was obtained through flash chromatography, elutingwith a gradient of 50-60% acetone in hexanes, in a yield of 37 mg (36%)as a white solid. ¹H NMR (500 MHz, d₆-DMSO) δ8.79 (s), 8.74 (s), 8.37(s), 8.11 (s), 7.62 (d), 7.47 (s), 7.43 (s), 7.30 (d), 7.13 (d), 7.14(d), 4.11 (t), 3.94 (s), 3.07 (t), 2.17 (s). R_(f) 0.14 (1:1hexanes/acetone).

EXAMPLE 13

[0228]

[0229] A suspension of 113 (from Example 5) (250 mg, 5.76 mmol) inCH₂Cl₂ (1 mL) was treated in a dropwise fashion at ambient temperaturewith several equivalents of trifluoroacetic acid and stirred for 90 min.The resulting solution was stripped in vacuo and tritrated with CH₂Cl₂and methanol. Pure product 168 was isolated by filtration in a yield of258 mg (99%). The ¹H NMR was consistent with that of the desiredproduct.

[0230] A suspension of 168 (250 mg, 0.55 mmol) in 21 mL of CH₂Cl₂/DMF(20:1 by volume) was treated with triethyl amine (193 μL, 1.38 mmol) andstirred at ambient temperature until homogeneity was reached. Thesolution was cooled to 0 C, treated with (S) 3-tetrahydrofuranyl-N-oxysuccinimidyl carbonate (635 mg, 0.608 mmol) and allowed to stirovernight with warming to ambient temperature. The mixture was pouredinto ethyl acetate (500 mL), washed with NaHCO₃(aq)(2×), water (2×), andbrine(1×), dried over Na₂SO₄ and stripped in vacuo. Pure product 120 wasisolated by tritration (30 mL CH₂Cl₂, 100 mL ether) in a yield of 212 mg(85%). The ¹H NMR was consistent with that of the desired product.

EXAMPLE 14 IMPDH Activity Inhibition Assay

[0231] We measured the inhibition constants of the compounds listed inTable III utilizing the following protocol:

[0232] IMP dehydrogenase activity was assayed following an adaptation ofthe method first reported by Magasanik. [Magasanik, B. Moyed, H. S. andGehring L. B. (1957) J. Biol. Chem. 226, 339]. Enzyme activity wasmeasured spectrophotometrically, by monitoring the increase inabsorbance at 340 nm due to the formation of NADH (ε340 is 6220 M⁻¹cm⁻¹). The reaction mixture contained 0.1 M Tris pH 8.0, 0.1 M KCl, 3 mMEDTA, 2 mM DTT, 0.1 M IMP and enzyme (IMPDH human type II) at aconcentration of 15 to 50 nM. This solution is incubated at 37° C. for10 minutes. The reaction is started by adding NAD to a finalconcentration of 0.1M and the initial rate is measured by following thelinear increase in absorbance at 340 nm for 10 minutes. For reading in astandard spectrophotometer (path length 1 cm) the final volume in thecuvette is 1.0 ml. The assay has also been adapted to a 96 wellmicrotiter plate format; in this case the concentrations of all thereagents remain the same and the final volume is decreased to 200 μl.

[0233] For the analysis of inhibitors, the compound in question isdissolved in DMSO to a final concentration of 20 mM and added to theinitial assay mixture for preincubation with the enzyme at a finalvolume of 2-5% (v/v). The reaction is started by the addition of NAD,and the initial rates measured as above. K_(i) determinations are madeby measuring the initial velocities in the presence of varying amountsof inhibitor and fitting the data using the tight-binding equations ofHenderson (Henderson, P. J. F. (1972) Biochem. J. 127, 321].

[0234] These results are shown in Table III. K_(i) values are expressedin nM. Category “A” indicates 0.01 to 50 nm activity, category “B”indicates 51-1000 nm activity, category “C” indicates 1001 to 10,000 nmactivity, category “D” indicates greater than 10,000 nm activity. Thedesignation “ND” is used where a given compound was not tested. TABLEIII Cmpd # K_(i) (nM) 1 C 2 C 3 B 4 D 5 C 6 C 7 B 8 C 9 C 10 C 11 C 12 C13 C 14 C 15 C 16 C 17 B 18 C 19 C 20 C 21 C 22 C 23 C 24 B 25 C 26 C 27C 28 C 29 D 30 C 31 D 32 D 33 D 34 C 35 C 36 C 37 C 38 D 39 D 40 C 41 C42 B 43 B 44 — 45 C 46 B 47 B 48 C 49 C 50 D 51 D 52 C 53 C 54 C 55 A 56B 57 B 58 C 59 A 60 B 61 D 62 C 63 C 64 B 65 B 66 C 67 C 68 B 69 B 70 C71 C 72 C 73 B 74 B 75 B 76 C 77 B 78 B 79 B 80 C 81 C 82 C 83 B 84 B 85B 86 C 87 D 88 C 89 C 90 C 91 C 92 C 93 A 94 B 95 C 96 B 97 A 98 B 99 A100 B 101 C 102 C 103 C 104 C 105 B 106 B 107 A 108 B 109 B 110 B 111 A112 B 113 A 114 B 115 B 116 A 117 B 118 C 119 A 120 A 121 A 122 A 123 A124 A 125 A 126 A 127 A 128 A 129 A 130 A 131 A 132 A 133 A 134 A 135 A136 A 137 B 138 A 139 B 140 A 141 A 142 A 143 B 144 B 145 A 146 A 147 A148 A 149 A 150 A 151 B 152 B 153 A 154 A 155 A 156 A 157 B 158 B 159 A160 A 161 A 162 A 163 B 164 B 165 A 166 D 167 B 168 B

EXAMPLE 15 Anti-Viral Assays

[0235] The anti-viral efficacy of compounds may be evaluated in variousin vitro and in vivo assays. For example, compounds may be tested in invitro viral replication assays. In vitro assays may employ whole cellsor isolated cellular components. In vivo assays include animal modelsfor viral diseases. Examples of such animal models include, but are notlimited to, models for HBV or HCV infection, the Woodchuck for HBVinfection, and chimpanzee model for HCV infection.

[0236] While we have described a number of embodiments of thisinvention, it is apparent that our basic constructions may be altered toprovide other embodiments which utilize the products and methods of thisinvention. Therefore, it will be appreciated that the scope of thisinvention is to be defined by the appended claims, rather than by thespecific embodiments which have been presented by way of example.

We claim:
 1. A method of inhibiting IMPDH activity in a mammalcomprising the step of administering to said mammal a compound of theformula:

wherein: A is selected from: (C₁-C₆)-straight or branched alkyl, or(C₂-C₆)-straight or branched alkenyl or alkynyl; and A optionallycomprises up to 2 substituents, wherein: the first of said substituents,if present, is selected from R¹ or R³, and the second of saidsubstituents, if present, is R¹; B is a saturated, unsaturated orpartially saturated monocyclic or bicyclic ring system optionallycomprising up to 4 heteroatoms selected from N, O, or S and selectedfrom the formulae:

wherein each X is the number of hydrogen atoms necessary to completeproper valence; and B optionally comprises up to 3 substituents,wherein: the first of said substituents, if present, is selected fromR¹, R², R⁴ or R⁵, the second of said substituents, if present, isselected from R¹ or R⁴, and the third of said substituents, if present,is R¹; and D is selected from C(O), C(S), or S(O)₂; wherein: each R¹ isindependently selected from 1,2-methylenedioxy, 1,2-ethylenedioxy, R⁶ or(CH₂)_(n)—Y; wherein n is 0, 1 or 2; and Y is selected from halogen, CN,NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂, NHR⁶, N(R⁶)₂, NR⁶R⁸, COOH,COOR⁶ or OR⁶; each R² is independently selected from (C₁-C₄)-straight orbranched alkyl, or (C₂-C₄)-straight or branched alkenyl or alkynyl; andeach R² optionally comprises up to 2 substituents, wherein: the first ofsaid substituents, if present, is selected from R¹, R⁴ and R⁵, and thesecond of said substituents, if present, is R¹; R³ is selected from amonocyclic or a bicyclic ring system consisting of 5 to 6 members perring, wherein said ring system optionally comprises up to 4 heteroatomsselected from N, O, or S, and wherein a CH₂ adjacent to any of said N,O, or S heteroatoms is optionally substituted with C(O); and each R³optionally comprises up to 3 substituents, wherein: the first of saidsubstituents, if present, is selected from R¹, R², R⁴ or R⁵, the secondof said substituents, if present, is selected from R¹ or R⁴, and thethird of said substituents, if present, is R¹; each R⁴ is independentlyselected from OR⁵, OC(O)R⁶, OC(O)R⁵, OC(O)OR⁶,OC(O)OR⁵, OC(O)N(R⁶)₂,OP(O)(OR⁶)₂, SR⁶, SR⁵, S(O)R⁶, S(O)R⁵, SO₂R⁶, SO₂R⁵, SO₂N(R⁶)₂, SO₂NR⁵R⁶, SO₃R⁶, C(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, NC(O)C(O)R⁶, NC(O)C(O)R⁵,NC(O)C(O)OR⁶, NC(O)C(O)N(R⁶)₂, C(O)N(R⁶)₂, C(O)N(OR⁶)R⁶, C(O)N(OR⁶)R⁵,C(NOR⁶)R⁶, C(NOR⁶)R⁵, N(R⁶)₂, NR⁶C(O)R¹, NR⁶C(O)R⁶, NR⁶C(O)R⁵,NR⁶C(O)OR⁶, NR⁶C(O)OR⁵, NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶, NR⁶SO₂R⁶, NR⁶SO₂R⁵,NR⁶SO₂ N(R⁶)₂, NR⁶SO₂NR⁵R⁶, N(OR⁶)R⁶, N(OR⁶)R⁵, P(O)(OR⁶)N(R⁶)₂, andP(O) (OR⁶)₂; each R⁵ is a monocyclic or a bicyclic ring systemconsisting of 5 to 6 members per ring, wherein said ring systemoptionally comprises up to 4 heteroatoms selected from N, O, or S, andwherein a CH₂ adjacent to said N, O, or S maybe substituted with C(O);and each R⁵ optionally comprises up to 3 substituents, each of which, ifpresent, is R¹; each R⁶ is independently selected from H,(C₁-C₄)-straight or branched alkyl, or (C₂-C₄) straight or branchedalkenyl; and each R⁶ optionally comprises a substituent that is R⁷; R⁷is a monocyclic or a bicyclic ring system consisting of 5 to 6 membersper ring, wherein said ring system optionally comprises up to 4heteroatoms selected from N, O, or S, and wherein a CH₂ adjacent to saidN, O, or S maybe substituted with C(O); and each R⁷ optionally comprisesup to 2 substituents independently chosen from H, (C₁-C₄)-straight orbranched alkyl, or (C₂-C₄) straight or branched alkenyl,1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH₂)_(n)—Z; wherein n is 0, 1or 2; and Z is selected from halogen, CN, NO₂, CF₃, OCF₃, OH,S(C₁-C₄)-alkyl, SO(C₁-C₄)-alkyl, SO₂(C₁-C₄)-alkyl, NH₂, NH(C₁-C₄)-alkyl,N((C₁-C₄)-alkyl)₂, N((C₁-C₄)-alkyl)R⁸, COOH, C(O)O(C₁-C₄)-alkyl orO(C₁-C₄)-alkyl; and R⁸ is an amino protecting group; and wherein anycarbon atom in any A, R² or R⁶ is optionally replaced by O, S, SO, SO₂,NH, or N(C₁-C₄)-alkyl.
 2. The method according to claim 1, wherein insaid compound, B has from 0 to 2 substituents.
 3. The method accordingto claim 1 or 2, wherein in said compound, B comprises at least a firstsubstituent and wherein said first substituent is R⁵.
 4. The methodaccording to claim 3, wherein in said compound, B is a monocyclicaromatic ring and said first substituent of B is a monocyclic aromaticring.
 5. A compound of the formula:

wherein: A, D, and B are as defined in claim 1; B is O or S; and G andG′ are independently selected from R¹ or H.
 6. A compound of theformula:

wherein K is selected from R¹ and R⁴; and A, D, R¹ and R⁴ are eachindependently as defined in claim
 1. 7. The compound according to claim6, wherein D is —C(O)—.
 8. The compound according to claim 6, wherein Kis (CH²)_(n)—Y.
 9. The compound according to claim 8, wherein K is OCH₃.10. A pharmaceutical composition comprising: a. a compound of theformula:

in an amount effective to inhibit IMPDH activity, wherein A, B and D areas defined in claim 1; b. an additional agent selected from animmunosuppressant, an anti-cancer agent, an anti-viral agent,antiinflammatory agent, antifungal agent, antibiotic, or ananti-vascular hyperproliferation agent; c. a pharmaceutically acceptableadjuvant.
 11. The composition according to claim 10, wherein in saidcompound, at least one B comprises at least a first substituent andwherein said first substituent is R⁵.
 12. A pharmaceutical compositioncomprising: a. a compound according to any one of claims 5 to 9 in anamount effective to inhibit IMPDH activity; and b. a pharmaceuticallyacceptable adjuvant.
 13. The pharmaceutical composition according toclaim 12, additionally comprising an additional agent selected from animmunosuppressant, an anti-cancer agent, an anti-viral agent,antiinflammatory agent, antifungal agent, antibiotic, or ananti-vascular hyperproliferation agent.
 14. A method for treating orpreventing IMPDH mediated disease in a mammal comprising the step ofadministering to said mammal a composition according to claim
 10. 15. Amethod for treating or preventing IMPDH mediated disease in a mammalcomprising the step of administering to said mammal a compositionaccording to either of claims 12 or
 13. 16. The method according toeither of claims 14 or 15, wherein said method is used to suppress animmune response and wherein said additional agent, if present, is animmunosuppressant.
 17. The method according to claim 16, wherein saidIMPDH mediated disease is an autoimmune disease.
 18. The methodaccording to either of claims 14 or 15, wherein the IMPDH mediateddisease is a viral disease and wherein said additional agent, ifpresent, is an anti-viral agent.
 19. The method according to either ofclaims 14 or 15, wherein the IMPDH mediated disease is a vasculardisease and wherein said additional agent, if present, is ananti-vascular hyperproliferation agent.
 20. The method according toeither of claims 14 or 15, wherein the IMPDH mediated disease is cancerand wherein said additional agent, if present, is an anti-cancer agent.21. The method according to either of claims 14 or 15, wherein the IMPDHmediated disease is an inflammatory disease and wherein said additionalagent, if present, is an anti-inflammatory agent.